👤 Tsung-Hsuan Lai

Despite advances in acute ischemic stroke (AIS) research, identifying reliable biomarkers and regulatory mechanisms remains challenging. We first identified AIS-related genes via extensive literature review, retrieved dataset GSE16561 from the Gene Expression Omnibus (GEO, https://ncbi.nlm.nih.gov/geo/), and performed differential/enrichment analyses. Bioinformatics verified N6-methyladenosine (m Show less

Breast cancer patients frequently experience debilitating cancer-related fatigue (CRF) during chemotherapy. Emerging evidence implicates the gut microbiota (GM) and the gut-brain axis in CRF pathogenesis, yet whether pre-chemotherapy GM profiles can predict CRF remains unclear. This prospective cohort study enrolled 100 breast cancer patients initiating chemotherapy. GM profiling and fatigue assessment (Visual Analogue Fatigue Scale, Cancer Fatigue Scale) were performed at baseline and the third chemotherapy cycle. Serum levels of neuroimmune-endocrine markers were also measured. Multivariate logistic regression was used to build a predictive model for moderate-to-severe CRF. Patients experiencing moderate-to-severe CRF at the third chemotherapy cycle demonstrated higher baseline Baseline GM characteristics predict the risk and severity of chemotherapy-induced CRF, potentially through modulation of neuroimmune-endocrine pathways via gut-brain axis. These findings underscore the potential role of GM as a predictive biomarker and a therapeutic target for chemotherapy-induced CRF. Show less

The activation of glial cells in the central nervous system plays an important role in the neural signaling of chronic pain and pruritus. However, their involvement in the neural signaling of chronic pain and pruritus in ACD remains to be investigated. To determine the effect of spinal glial cell activation in the coexistence of chronic pain and pruritus in the ACD model, we observed spinal glial cell activation in a mouse model of ACD induced by SADBE. Square acid dibutyl ester (SADBE) was employed to establish ACD model mice and monitor the activation of spinal cord glial cells. Additionally, the Gene Expression Omnibus (GEO) database was utilized to analyze potential mechanisms. In the ACD model, the behaviors of licking and biting within 35 days after modeling were significantly increased. The expression levels of Iba-1, BDNF, LCN2, GRPR, and GFAP differed significantly from those of the control group. In addition, through GEO data analyses, a strong correlation has been found between pain and IFN-γ. Similarly, in vitro experiments revealed that IFN-γ increased the expression of Iba-1, CD16, and BDNF in BV2 cells and the release of LCN2 in primary astrocytes, thus activating spinal cord glial cells. IFN-γ also induced the phosphorylation of JAK1/STAT1 and the expression of IFNGR1 in BV2 cells and primary astrocytes. Collectively, the above findings suggest that the coexistence of chronic pain and pruritus in the ACD model is associated with the activation of spinal microglia and astrocytes. The underlying mechanism involves the binding of IFN-γ to its receptor IFNGR1, which is accompanied by the upregulation of JAK1/STAT1 signaling pathway phosphorylation. Show less

Early pregnancy loss (EPL), a spontaneous death of the embryo or foetus occurring within the first trimester, is a major challenge for human reproduction with profound adverse consequences for women's health. Currently, reliable blood-based biomarkers for EPL remain limited. Therefore, there is an urgent need to discover novel biomarkers for EPL using a multi-omics-based approach to facilitate early detection and timely management. In the discovery cohort, 40 patients with EPL and 40 healthy pregnancies (HP) at 7-13 weeks of gestation were enrolled. Serum proteins and metabolites were assayed by Olink® technology and ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS), respectively. Biomarkers were defined by false discovery rate (FDR) < 0.05 and fold change (FC) > 1.2. Random forest (RF) and logistic regression (LR) models incorporating selected biomarkers were employed to develop diagnostic models for EPL. In the external validation cohort, we prospectively enrolled 142 pregnancies at 7-10 gestational weeks, including 47 subjects who subsequently developed EPL and 95 pregnancies with full-term birth. Serum levels of selected biomarkers were quantified by ELISA. The combined proteomics and metabolomics screening identified 26 proteins and 21 metabolites significantly changed in the EPL group and tightly associated with EPL-related clinical phenotypes, with functional enrichment in immunoregulation and lipid oxidation processes. Moreover, integrating serum levels of angiopoietin-like 4 (ANGPTL4), programmed death-ligand 1 (PD-L1), neutrophil%, and lymphocyte% achieved an AUC of 0.944 (95% CI: 0.835-1.000) in the random forest model and 0.954 (95% CI: 0.875-1.000) in the logistic regression model to discriminate EPL from HP. Importantly, this four-biomarker model achieved an AUC of 0.857 (95% CI: 0.747-0.968) in the random survival forest model and a C-index of 0.804 (95% CI: 0.685-0.973) in the validation cohort for EPL prediction. Our integrative omics study reveals a panel of potential circulating biomarkers for EPL, which further offer mechanistic insights into EPL pathogenesis, including impaired maternal immune tolerance and dysregulated lipid metabolism pathways. Moreover, the newly identified biomarkers exhibit promising diagnostic and predictive performance for EPL, underscoring its clinical translational value for human reproduction and maternal-foetal health. This study was supported by Research Grants Council (RGC) Germany/Hong Kong Joint Research Scheme (G-CUHK415/25), 1+1+1 CUHK-CUHK(SZ)-GDST Joint Collaboration Fund (2025A0505000077), CUHK HOPE BWCH Collaborative Medical Research Fund (CF2025002), Shenzhen Medical Research Fund (C2501040), and Shenzhen Science and Technology Program (RCYX20210609104608036). Show less

Clinical application of mesenchymal stem cells for endometrial repair has been hampered by variability in cell quality, large-scale production, and uncertainty regarding the optimal delivery route. In this study, we investigated the therapeutic potential of clinical-grade human embryonic stem cell-derived immunity-and-matrix-regulatory cells (IMRCs) for treating refractory moderate-to-severe intrauterine adhesion (IUA). In a rabbit IUA model, sub-endometrial injection of IMRCs significantly reduced fibrosis and enhanced endometrial angiogenesis, outperforming uterine perfusion. Transcriptomic analysis revealed distinct pro-angiogenic gene expression profiles between the two delivery routes. In vitro, IMRCs co-cultured with endometrial stromal cells (ESCs) markedly enhanced angiogenic potential compared to either cell type alone. Protein array analysis of the co-culture supernatant showed elevated levels of angiogenic factors, with functional assays confirming that inhibition of ANGPTL4, a non-canonical pro-angiogenic mediator, impaired angiogenesis. In a first-in-human, single-center, phase 1 dose-escalation trial involving 18 patients with refractory IUA, high-dose sub-endometrial IMRC injection promoted angiogenesis, reduced uterine scarring, and improved pregnancy outcomes, with no safety concerns observed over 3 years of follow-up. These findings highlight the translational promise of IMRCs as a novel therapeutic strategy for endometrial regeneration in severe IUA. Show less

ApoB (apolipoprotein B)-containing lipoproteins are causal risk factors for atherosclerotic coronary artery disease (CAD). Since human cathelicidin LL-37 binds to ApoB-100 in this pathological context, we investigated whether the circulating LL-37-ApoB-100 complex could serve as a biomarker for CAD. We performed surface plasmon resonance and protein-protein docking to demonstrate the direct LL-37-ApoB-100 interaction. We developed a specific polyclonal antibody against the complex and measured its levels in human atherosclerotic plaques and plasma, as well as in We identified that LL-37 directly interacted with multiple distinct binding sites on ApoB-100. Plasma levels of LL-37-ApoB-100 complex were significantly elevated in human patients with atherosclerosis. Consistently, levels of this complex were positively correlated with atherosclerotic plaque area in Circulating LL-37-ApoB-100 levels are strongly associated with angiographically documented CAD, highlighting LL-37-ApoB-100 as an independent predictor for CAD. Show less

To develop and validate a prediction model for in-hospital cardiogenic shock (CS) after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) based on machine learning (ML) algorithms. A total of 1608 AMI patients admitted to the First Hospital of Lanzhou University during 2023 and 2024 were retrospectively enrolled in this study. The 851 patients from 2023 were randomly divided into a training set ( LASSO regression initially identified 13 candidate features, while the random forest (RF) model demonstrated the best predictive performance in the training set. Following Boruta refinement, seven key features were retained, leading to the construction of an updated RF model. This model achieved an AUROC of 0.906, an accuracy of 0.977, a precision of 0.900, a sensitivity of 0.643, a specificity of 0.996, and a F1 score of 0.750 on the internal validation set. Temporal external validation at the same center showed an AUROC of 0.988, an accuracy of 0.967, a precision of 0.701, a sensitivity of 0.904, a specificity of 0.972, and a F1 score of 0.790. Furthermore, the model demonstrated excellent calibration, with a Brier score of 0.023 and 0.027. The SHAP analysis ranked feature importance as Killip class, D-dimer (DD), creatinine (Crea), alanine aminotransferase (ALT), apolipoprotein B/A (APOB/A), diastolic blood pressure (DBP) and lactate (Lac). We developed and validated a RF model based on seven key variables—Killip class, DD, Crea, ALT, APOB/A, DBP and Lac—that serves as a predictive tool for identifying the risk of in-hospital CS in AMI patients post-PCI. Additionally, we created an online prediction application using Streamlit, which facilitates the implementation of this model into clinical practice. Show less

Dysregulation of low-density lipoprotein (LDL) cholesterol is strongly correlated with the risk of metabolic dysfunction-associated steatotic liver disease. Endogenous molecules targeting LDL clearance play crucial roles in the progression of liver steatosis. Human cathelicidin LL-37 can form complexes with lipoproteins, but whether these complexes regulate lipoprotein-driven cholesterol metabolism is not clear. Here, we find that cathelicidin LL-37 binds to LDL via apolipoprotein (Apo)B-100 domains, enhancing the solubility of ApoB-100 and inhibiting the modifications and aggregation of LDL. LL-37-LDL interaction promotes LDL uptake through LDL receptor (LDLR) both in hepatocytes and macrophages. This interaction also promotes LDL cholesterol clearance by facilitating cholesterol excretion and cholesterol efflux. In Apoe Show less

This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates. Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96% in models with and without APOE ε4. These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status. Show less

Atherosclerosis (AS) is a chronic inflammatory disease driven significantly by metabolic reprogramming (MR). However, the core MR-related genes and their specific functions in AS remain incompletely understood, thus creating an urgent need for reliable diagnostic and therapeutic biomarkers. Two AS-related microarray datasets (GSE100927 and GSE28829) were integrated and normalized. Differential expression analysis identified differentially expressed genes (DEGs), which were intersected with an MR-related gene set to obtain MR-related DEGs (MRDEGs). Functional enrichment analyses-including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses-were conducted. Subsequently, weighted gene co-expression network analysis (WGCNA) was combined with multiple machine learning algorithms to screen for hub genes. These candidate genes were further validated using an external dataset (GSE43292) and evaluated via receiver operating characteristic (ROC) curve analysis. Additionally, a multi-gene diagnostic model was constructed and assessed using both nomogram and SHAP analysis. Single-gene Gene Set Enrichment Analysis (GSEA) elucidated the biological functions of core genes. Immune infiltration and single-cell analyses investigated microenvironment remodeling. Moreover, transcription factor (TF) prediction via hTFtarget, integrated with transcriptome sequencing of human umbilical vein endothelial cells (HUVECs), identify upstream regulators. Finally, Experimental validation was performed in ApoE We identified 57 MRDEGs and selected four core genes-LYN, FABP5, MMP9, and ANPEP-which demonstrated high diagnostic value. The multi-gene model showed strong clinical predictive performance. GSEA further revealed significant involvement of these genes in immune-inflammatory pathways. Immune infiltration and single-cell analyses confirmed substantial immune microenvironment remodeling and altered cell-cell communication. EGR1 was identified as a key upstream transcription factor. Ultimately, Experimental validation in ApoE This study identifies LYN, FABP5, MMP9, and ANPEP as core MR-related genes in AS, clarifies their roles in immune microenvironment regulation, and confirms their value as diagnostic biomarkers, thereby providing new insights for precise diagnosis and targeted therapy of AS. Show less

The We employed a multi-omics approach, combining snRNA-seq and locus-specific epigenetic analysis, alongside microglia-specific gene manipulation in ApoE-targeted replacement (TR) mice. Primary microglia were challenged with cholesterol to simulate lipid overload conditions. In mid-life ApoE4-TR mice, microglia within the dentate gyrus developed pronounced lipid droplet accumulation, concurrent with impaired Aβ clearance and a pro-inflammatory shift. snRNA-seq unveiled a unique microglial cluster in ApoE4 mice, enriched for lipid-metabolism genes and marked by the pronounced downregulation of the hub gene Asxl1. Mechanistically, ApoE4 attenuated the Asxl1–LXRα interaction, leading to reduced H3K4me3 occupancy at promoters of lipid-efflux genes such as Abca1. Crucially, CRISPR-mediated, microglia-specific overexpression of Asxl1 restored H3K4me3 levels, normalized cholesterol efflux, and rescued Aβ phagocytic deficits in vivo. Our findings define an epigenetic pathway whereby ApoE4 drives microglial dysfunction via the Asxl1–LXRα–H3K4me3 axis, fostering the LDAM phenotype. Enhancing Asxl1 function presents a promising therapeutic avenue for countering ApoE4-mediated pathogenesis in AD. The online version contains supplementary material available at 10.1186/s12974-026-03740-3. Show less

Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neuroprotective axis in which macrophages deploy apolipoprotein E (APOE) to transfer intracellular lipids to neighboring cells, especially fibroblasts. Genetic ablation of The online version contains supplementary material available at 10.1186/s12974-026-03756-9. Show less

Alzheimer disease (AD) pathology may begin decades before symptoms. Genetic factors, such as APOE ε4 carrier status and polygenic risk scores (PRS), influence AD risk, but their roles in cognitive decline among Asian populations remain unclear. To evaluate whether APOE ε4 carrier status and a non-APOE polygenic risk score (PRS_ADnapoe) are associated with age-related cognitive decline in community-dwelling older adults in Taiwan. This prospective cohort study used data from 2 assessment waves of the Healthy Aging Longitudinal Study in Taiwan, spanning 2009 to 2019. Participants were aged 55 years and older and had both genetic data and Mini-Mental State Examination (MMSE) scores. Data analyses were conducted from August to December 2025. APOE ε4 carrier status (noncarrier, heterozygote, homozygote) and PRS_ADnapoe score, derived from genome-wide association summary statistics excluding APOE variants. The primary outcome was change in MMSE scores, which were assessed cross-sectionally and longitudinally, modeled with mixed-effects regression accounting for age-related effects and covariates including sex, education, smoking, and population structure. Among 4392 participants (mean [SD] age, 68.2 [7.8] years; 2359 [53.7%] women), 723 (16.5%) were APOE ε4 heterozygotes and 33 (0.8%) were APOE ε4 homozygotes. Over a mean (SD) follow-up of 6.3 (0.9) years, the mean (SD) annual MMSE decline was -0.2 (0.5). APOE ε4 carriage was associated with a significantly steeper quadratic age-associated decline in MMSE scores compared with noncarriers (estimate, -0.005; SE, 0.001; P = .001). This association was strongest among homozygotes (estimate, -0.017; SE, 0.008; P = .03), with MMSE trajectories diverging after approximately age 70 years. In contrast, PRS_ADnapoe scores were not associated with MMSE decline. Sensitivity analyses restricted to participants with 2-wave data and adjusted with inverse probability of censoring weighting confirmed these findings. In this cohort study of middle-aged and older adults in Taiwan, APOE ε4 carriage, particularly homozygosity, was associated with accelerated age-related cognitive decline detectable after age 70 years, whereas non-APOE polygenic risk was not associated with cognitive decline over the current follow-up. These results highlight the potential utility of early genetic risk awareness and support consideration of targeted preventive strategies for APOE ε4 carriers. Show less

Given the complexity of dementia, the inconsistent evidence on statins and dementia highlights the need for robust methods to assess heterogeneous treatment effects (HTEs). We emulated a target trial using UK Biobank comparing statin initiators and non-initiators aged ≥55 years. Marginal structural models were fitted to estimate 5-year adjusted risk difference (aRD). We used iterative causal forest, a causal machine learning subgrouping algorithm, to identify subgroups with HTEs. Among 18,366 participants, the overall aRD for all-cause dementia was -1.0‰ (95% CI: -4.2‰ to 2.3‰). We identified subgroups by polygenic risk score for Alzheimer's disease (AD) excluding apolipoprotein E (APOE) genotype ("non-APOE PRS"). Participants with high non-APOE PRS showed cognitive benefit (all-cause dementia: aRD -5.9‰, 95% CI: -8.1‰ to 1.2‰; AD: aRD -5.0‰, 95% CI: -8.2‰ to -0.2‰). Participants with high non-APOE PRS may benefit from statins, suggesting genetic susceptibility beyond APOE could modify statins' cognitive effects. Show less

Atherosclerosis (AS) serves as the pathological foundation for numerous cardiovascular and cerebrovascular diseases and is highly comorbid with depression. The mechanisms underlying this co-morbidity are exceptionally complex, posing significant challenges to effective clinical treatment. Consequently, our study aims to explore the potential biomarkers and mechanisms involved in developing atherosclerosis co-depression disease. We performed differential expression analysis, protein-protein interaction analysis, Gene Ontology (GO) function enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on co-differentiated genes using AS and depression-related datasets from the GEO database. Potential biomarkers were identified through ROC curve analysis. To evaluate the effectiveness of the model, we established an animal model of AS comorbid with depressive disorder and performed a series of assessments, including the sugar-water preference test, open field test, tail suspension test, lipid profile analysis, and pathological examination of aortic sections. Additionally, RNA sequencing analysis of brain tissue, Golgi staining, and detection of synaptic function-related proteins were performed in AS comorbid depressed mice. Finally, in vitro cellular experiments were conducted to further validate the molecular targets and underlying mechanisms. We identified 968 differentially expressed genes associated with AS and 472 differentially expressed genes associated with depression, with 30 genes co-differentially expressed. Protein-protein interaction (PPI) analysis revealed that CCR5, CCR2, NPY, and OPRM1 were strongly associated with AS co-depression, while ROC analysis indicated that Shank2, MDGA2, and S100B were diagnostic markers for AS with depression. Differentially expressed genes were closely associated with the chemokine signaling pathway, neuroactive ligand-receptor interaction, cytokine-cytokine receptor interaction, and taste transduction. Animal studies demonstrated that ApoE Our study identified seven candidate AS co-depression biomarkers and verified that inflammation-induced damage to synaptic plastic rows is an important mechanism of AS co-depression, providing new insights into the diagnosis and treatment of AS co-depression disorders. Show less

Calcific aortic valve disease (CAVD) involves pathological mineralization, but the roles of chemokine signaling and ferroptosis remain unclear. This study investigated the regulatory function of C-C motif chemokine ligand 5 (CCL5) in CAVD progression via the chemokine pathway and ferroptosis. Bioinformatics analysis and single-cell RNA sequencing analysis were performed to identify hub genes and potential cell types. Human aortic valve interstitial cells (VICs) were treated with osteogenic medium (OM) to induce calcification. Apoe CCL5 was identified as a key hub gene in CAVD. Knockdown of CCL5 significantly attenuated OM-induced VICs calcification, osteogenic differentiation, oxidative stress, and ferroptosis. Similar protective effects were observed in vivo, with reduced valve thickening and calcification in Apoe CCL5 promoted CAVD progression by activating the chemokine signaling pathway to induce ferroptosis. Targeting CCL5 may offer a novel therapeutic strategy for CAVD. Show less

To assess the association between hepatitis C virus (HCV) infection and cognitive impairment among seniors in Taiwan, building on our previous findings from a cross-sectional study. Retrospective cohort study. Taiwan Biobank. 326 participants with positive serum anti-HCV and a control group of 8753 with negative HCV free of cognitive impairment were assessed by the Mini-Mental State Examination at baseline. The association between HCV infection and cognitive impairment was evaluated using Cox proportional hazard models. The analysis was adjusted for age, sex, education, BMI, hypertension, cirrhosis, depression, estimated glomerular filtration rate, APOE genotype, and recruitment periods. Anti-HCV positive patients showed a significantly higher incidence of cognitive impairment compared to anti-HCV negative individuals (14.28 vs. 7.21 per 1000 person-years, P = 0.004). After adjusting for covariates, HCV infection was significantly associated with an increased risk of developing cognitive impairment (adjusted HR [aHR]: 1.80, 95% confidence interval [CI]: 1.12-2.90). Subgroup analyses for individuals diagnosed prior to the public direct-acting antivirals reimbursement in 2017 and with high antibody titres (sample/cutoff ratio ≥ 5), the elevated risk of cognitive impairment remained statistically significant, with aHRs of 1.69 (95% CI: 1.04-2.75) and 1.81 (95% CI: 1.11-2.96) respectively. Additionally, HCV patients carrying the APOE ɛ4 allele had a marginally higher risk (aHR: 2.60, 95% CI: 0.96-7.08, P = 0.06). In Taiwan, our findings strengthen evidence that individuals above the age of 60 with HCV infections are at a greater risk of developing cognitive impairment than their counterparts, who were HCV negative. Show less

To investigate the effects of SLCO1B1, apolipoprotein E (APOE) and ABCG2 gene polymorphisms on the lipid-modulating efficacy of rosuvastatin. Systematic searches were conducted in PubMed, Cochrane Library, Embase, Web of Science, PharmGKB, CNKI, VIP, and Wanfang databases (from database establishment to 1 March 2025). Studies on the correlation between SLCO1B1, APOE, ABCG2 gene polymorphisms and the lipid-modulating efficacy of rosuvastatin were collected, and meta-analysis was performed using RevMan 5.4 software. A total of 16 studies involving 6167 patients were included, covering APOE (p.C130R/rs429358, p.R176C/rs741), SLCO1B1 (p.V174A/rs4149056, p.N130D/rs2306283), and ABCG2 (p.Q141K/rs2231142) genes. The results showed that SLCO1B1 [AG+GG vs. AA, mean difference = -4.36, 95% confidence interval (CI): -7.92 to -0.80, P = 0.02], APOE (E2 vs. E3, mean difference = -5.58, 95% CI: -8.04 to -2.51, P < 0.00001] and ABCG2 (CA+AA vs. CC, mean difference = -7.07, 95% CI: -9.47 to -4.68, P < 0.00001) genotypes all significantly affected statin-induced low-density lipoprotein cholesterol (LDL-C) reduction; patients with ABCG2 CA+AA genotype had statistically significant differences in total cholesterol level changes (mean difference = -7.15, 95% CI: -8.78 to -5.53) and triglyceride level changes (mean difference = -7.37, 95% CI: -10.91 to -3.83) (both P < 0.05). The lipid-lowering efficacy of rosuvastatin (especially the reduction of LDL-C level) is significantly affected by the polymorphisms of SLCO1B1 (c.388A>G), ApoE (c.388T>C, c.526C>T) and ABCG2 (c.421C>A) genes. Show less

Vascular smooth muscle cell (VSMC)-derived foam cell formation is a major contributor to atherosclerosis progression and plaque instability. Meteorin-like protein (METRNL), a secreted organokine with known metabolic and anti-inflammatory effects, has been linked to cardiovascular protection, but its role in atherosclerosis is not well defined. This study investigated the function of METRNL in VSMC-derived foam cell formation and atherosclerosis and explored the underlying signaling mechanisms. ApoE METRNL levels declined during atherosclerosis progression and were restored during regression. METRNL selectively inhibited foam cell formation in VSMCs-but not in macrophages-by downregulating CD36-mediated cholesterol uptake and suppressing endoplasmic reticulum stress through KIT signaling. Deletion of KIT specifically in smooth muscle cells abolished these protective effects. The transcription factor SP1 was found to bind directly to the METRNL promoter and enhance its expression. Clinically, lower serum METRNL levels were independently associated with increased risk and severity of acute coronary syndrome. METRNL protects against VSMC foam cell formation and atherosclerosis by enhancing KIT signaling, thereby reducing ER stress and subsequent cholesterol uptake. These findings position METRNL as a potential therapeutic target and biomarker for atherosclerotic cardiovascular disease. Show less

Biallelic DIAPH1 mutations are linked to hereditary microcephaly syndrome, yet the underlying pathogenic mechanism remains unelucidated. This study aimed to clarify how DIAPH1 biallelic mutations cause microcephaly and visual impairment, focusing on the gene's regulatory role in the Wnt/β-catenin signaling pathway. Whole exome sequencing was performed on a patient's peripheral blood to identify DIAPH1 mutations. A zebrafish model was established by microinjecting mutant human DIAPH1 cDNA into one-cell embryos (no zebrafish DIAPH1 homolog exists). Phenotypic analyses (morphology, neuronal axon growth, behavior) and quantitative real-time PCR for Wnt/β-catenin pathway genes were conducted. Data were mean ± SEM; statistical tests (Student's t-test, ANOVA, χ²) used GraphPad Prism 5.0 (P < 0.05, P < 0.0001 for significance). Compound heterozygous DIAPH1 mutations (c.1051 C > T, p.R351X; c.609delA, p.E203E fs*19) were found and associated with clinical symptoms. Mutant DIAPH1 zebrafish showed abnormal eye shape, shortened body length, axis defects, impaired motor axon growth, reduced locomotor activity, upregulated WNT8A, WNT9A, LRP5, LRP6, and downregulated AXIN1, AXIN2, β-CATENIN, indicating excessive Wnt/β-catenin pathway activation. DIAPH1 compound heterozygous mutations may trigger microcephaly and visual impairment by abnormally activating the Wnt/β-catenin pathway. The zebrafish model provides a reliable in vivo system for studying DIAPH1-related microcephaly, advancing understanding of hereditary primary microcephaly pathogenesis and potential therapeutic target exploration. Show less

Alzheimer's disease (AD) is marked by amyloid-β (Aβ) accumulation, tau pathology, and neuroinflammation. The β-site APP cleaving enzyme 1 (BACE1) is a key driver of Aβ production, while the NLRP3 inflammasome mediates microglial inflammatory responses. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase, is upregulated in AD, yet its role in disease mechanisms remains unclear. Here, we show that HDAC6 promotes BACE1 protein stability through direct deacetylation of its C-terminal lysine (K501), thereby increasing Aβ production. HDAC6 also facilitated NLRP3 inflammasome activation in microglia, increasing IL-1β production in a catalytic domain-dependent manner. HDAC6 deficiency in 5xFAD mice reduced BACE1 accumulation, Aβ deposition, ASC speck formation, and IL-1β levels, accompanied by improved cognitive performance. Transcriptomic profiling further revealed downregulation of disease-associated microglial and neurotoxic astrocyte signatures alongside enrichment of synaptic pathways. These findings establish HDAC6 as a dual regulator of Aβ production and neuroinflammation, highlighting it as a promising therapeutic target in AD. Show less

Chemical investigation of the soft coral Sclerophytum humesi led to the discovery of (±)-norsclerohumin A (1), a pair of enantiomeric norsesquiterpenoids possessing an unprecedented oxatricyclo[7.2.1.0 Show less

Endometriosis is a heterogeneous chronic inflammatory disorder associated with substantial diagnostic delay and limited therapeutic options, highlighting the need of robust non-invasive biomarkers and actionable molecular targets to complement existing low-sensitivity tests. To identify conserved pathogenic mechanisms with translational potential, here, we uniformly reprocessed three independent the Gene Expression Omnibus (GEO) microarray cohorts (GSE7305, GSE25628, and GSE11691) and applied a strict, directionally consistent intersection strategy to identify conserved transcriptional signals. We identified 262 consensus differentially expressed genes enriched for immunity/inflammation, cell adhesion and migration, and angiogenesis, consistent with key biological hallmarks of lesion establishment and persistence. Protein-protein interaction topology prioritized 11 highly connected hub genes ( Show less

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide despite intensive lipid-lowering therapy. Residual cardiovascular risk persists even in patients achieving optimal lipoprotein-cholesterol (LDL-C) levels, indicating that additional lipid mediators contribute to disease progression. Lysophosphatidylcholine (LPC), a bioactive lysophospholipid generated from phosphatidylcholine by cytosolic or lipoprotein-associated phospholipase A₂ (PLA₂), has emerged as a critical mediator linking dyslipidemia, inflammation, and vascular injury. LPC is highly enriched in oxidized LDL (oxLDL), electronegative LDL (LDL(-)), and lipoprotein(a) [Lp(a)], all of which represent highly atherogenic lipoprotein subclasses. This review delineates the metabolic origins of LPC, its transport via LDL, VLDL, and albumin, and its accumulation within atherosclerotic plaques. LPC promotes endothelial dysfunction, monocyte recruitment, foam-cell formation, and platelet activation, collectively driving plaque development and instability. Elevated LPC levels are consistently observed in metabolic disorders such as type 2 diabetes mellitus (T2DM) and non-alcoholic steatohepatitis (NASH), both of which exacerbate ASCVD risk. Although statins, ezetimibe, and PCSK9 inhibitors effectively lower LDL-C, they do not directly target LPC or its downstream inflammatory pathways. Clinical trials of lipoprotein-associated PLA₂ inhibitors (e.g., Darapladib) failed to reduce cardiovascular events, underscoring the complexity of LPC-related signaling. Future therapeutic approaches may involve enhancing lysophospholipase A Show less

Identifying high-performing advanced practice nursing roles and understanding the factors that contribute to their effectiveness are critical for advancing professional development, optimizing workforce deployment, and ensuring long-term sustainability in nursing. This study aimed to (1) identify distinct latent profiles of advanced practice nursing among specialist nurses in mainland China, (2) quantitatively examine the individual and contextual factors associated with high performance, as characterized by these profiles, and (3) qualitatively confirm the significant factors using explanatory semistructured interviews in the high-performance groups. A mixed-methods sequential explanatory design was used, in which quantitative data were collected first and subsequently explained through qualitative interviews. Certified specialist nurses from 16 hospitals across urban and rural areas of Shanghai were included. Latent profile analysis (LPA) was conducted using the five domains from the Advanced Practice Role Delineation tool as manifest indicators to classify nurses into distinct performance profiles. Multinomial logistic regression was used to examine potential determinants (e.g., job position) of group membership. Additionally, a backpropagation neural network (BPNN) was developed to rank the importance of contributing factors. Specialist nurses identified as high performers in the quantitative phase were purposively sampled for explanatory semistructured qualitative interviews. Three latent profiles emerged: high performance (26.1%), moderate performance (46.3%), and low performance (27.6%). Compared to APNs, staff nurses had significantly lower odds of belonging to the high-performance group ( Identifying the profiles of advanced practice nursing roles provides valuable insights for optimizing APN performance and informing targeted management and policy strategies. High-performing specialist nurses are positioned at the nexus of individual capability, interdisciplinary collaboration, and institutional support. Show less

Lipoprotein(a) [Lp(a)] is a recognized risk factor for atherosclerotic cardiovascular disease (ASCVD), but the shape and potential nonlinearity of its association remain uncertain. We assessed the linear and nonlinear associations between Lp(a) levels and ASCVD risk using observational and Mendelian randomization (MR) approaches. We analyzed 351,858 UK Biobank participants (2006-2023), stratified into Lp(a) percentiles: <70th, 70th-<80th, 80th-<90th, and ≥90th. Outcomes included ASCVD events from hospital, primary care, self-report, and death registry data. Cox models estimated the hazard ratios (HRs). MR analyses used a polygenic risk score from 10 Lp(a)-associated single-nucleotide polymorphisms, with nonlinearity tested by doubly ranked MR. Higher Lp(a) levels were associated with increased ASCVD risk. Compared with the <70th percentile, adjusted HRs (95% confidence interval) were 1.11 (1.07-1.16), 1.18 (1.14-1.22), and 1.25 (1.21-1.30) for the 70th-<80th, 80th-<90th, and ≥90th groups. Kaplan-Meier curves diverged early by group. Spline models suggested nonlinearity with an inflection near 130 nmol/L (P=0.007). MR showed a 2% higher ASCVD risk per 10 nmol/L genetically predicted Lp(a) (P<2×10 Elevated Lp(a) concentrations were causally associated with ASCVD risk, showing a predominantly graded relationship with possible nonlinearity at very high levels, supporting routine Lp(a) measurement and the development of Lp(a)-lowering therapies. Show less

China's total fertility rate has reached a critically low level, dropping to approximately 1.0 by the end of 2023which is significantly below the population replacement level of 1.5. This decline reflects a marked reduction in fertility intention among reproductive-aged women, exacerbating population aging and threatening long-term labor supply and social sustainability. Despite policy adjustments and governmental support initiatives, intended outcomes have not been realized. Current literature largely focuses on isolated determinants of fertility intention, overlooking heterogeneity within the population. Moreover, the pathways through which psychosocial factors operate across different subgroups remain poorly understood. Data for this study were derived from the 2021 Psychological and Behavioral Investigation of Chinese Residents (PBICR 2021), a nationally representative cross-sectional survey. Latent profile analysis (LPA) was employed to identify subtypes of fertility intention among reproductive-aged women, followed by multinomial logistic regression, which examined factors associated with different profiles. Among 2,973 reproductive-aged female participants, three distinct fertility intention profiles were identified via latent profile analysis: the Fertility Intention Decline Group (25.1%), the Low Fertility Intention Group (51.3%), and the High Fertility Intention Group (23.6%). Multinomial logistic regression analysis revealed that, compared with the Fertility Intention Decline Group, the Low Fertility Intention Group was significantly associated with family type, aged 20-40 years, residential location, having 2 children, and retirement status (all Fertility intention among reproductive-aged women demonstrates significant heterogeneity. This study identified three distinct latent profiles, each characterized by unique patterns of influencing factors. The findings highlight the necessity of moving beyond one-size-fits-all policy approaches and emphasize the importance of developing tailored interventions that account for the specific characteristics and determinants of each subgroup. Show less

From a positive psychology perspective, this study aimed to identify the latent profiles of spiritual well-being and analyze the serial mediation mechanism of family care and spiritual coping in the relationship between spiritual well-being and health-related quality of life (HRQoL). The findings are intended to inform strategies for improving the spiritual well-being of maintenance hemodialysis (MHD) patients. A cross-sectional design was employed with 220 MHD patients recruited from two tertiary hospitals in Guangdong, China (August 2023-January 2024). Assessments were conducted using the Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being Scale (FACIT-SP-12), Family Care Index, Spiritual Coping Questionnaire (SCQ), and Short Form-12 Health Survey (SF-12). Latent profile analysis (LPA) was employed to identify heterogeneous subgroups based on spiritual well-being. A chain mediation model was then used to examine the mediating effects of family care and spiritual coping. HRQoL scores averaged 56.50 ± 22.29. Significant correlations emerged: spiritual well-being ( Spiritual well-being indirectly influences the quality of life in MHD patients through the serial mediation of family care and spiritual coping. Clinicians should recognize the heterogeneity in spiritual well-being and integrate routine spiritual screening into nursing assessments to identify patients with low spiritual well-being. It is recommended to develop family-based education and support programs, along with interventions that combine family care and spiritual coping strategies, so as to improve patients' long-term health outcomes. Show less

This study aims to identify the latent profiles of sense of coherence (SOC) in patients with advanced cancer and explore its influencing factors encompassing sociodemographic and clinical characteristics, and generalized resistance resources (GRRs). A cross-sectional study of 262 patients with advanced cancer was conducted by convenience sampling in Guangzhou, China, from September 2023 to July 2024. Data were collected including sociodemographic and clinical characteristics, SOC-13, Revised Life Orientation Test (LOT-R), Rosenberg Self-Esteem Scale (RSES), Inner Peace State Scale (IPSS), Gratitude Questionnaire-6 (GQ-6), and Social Support Rating Scale (SSRS). Statistical analysis was performed using latent profile analysis (LPA) and multivariate logistic regression analysis. Three latent profiles of SOC were identified: low SOC and low comprehensibility group (29.01%), moderate SOC and high meaningfulness group (40.08%), and high SOC and high manageability group (30.91%). This study found that SOC was impacted by self-perceived severity of the disease and GRRs including optimism, self-esteem, and inner peace ( SOC in patients with advanced cancer exhibited different characteristics. Enhancing positive disease perception and GRRs including optimism, self-esteem, and inner peace may be effective strategies for improving their SOC. Healthcare professionals can formulate strategies such as tailored health education, symptom management, and positive psychological interventions to enhance SOC in patients with advanced cancer. Show less